JP2022505194A - 組織常在メモリー様t細胞を生成するための方法及びその使用 - Google Patents
組織常在メモリー様t細胞を生成するための方法及びその使用 Download PDFInfo
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Abstract
Description
本願は、2018年10月18日に出願された米国仮特許出願第62/747,523号及び2019年5月10日に出願された米国仮特許出願第62/846,270号の利益を主張し、これら双方の全体は参照により本明細書中に援用される。
8KB(Microsoft Windows(登録商標)において測定された時)であり、2019年10月17日に作成された「UTFCP1408WO_ST25.txt」という名称のファイル中に含まれる配列表は、本明細書とともに電子申請により出願され、参照により本明細書中に援用される。
本発明は、一般に薬学及び免疫学の分野に関する。より詳細には、それは組織常在メモリー様T細胞を生成するための方法及びその使用に関する。
組織常在メモリー細胞(TRM)は、ウイルス性疾患に対する局所的なフロントライン防御において重要であるメモリーT細胞の最近同定されたサブセットである。最近の報告では、この表現型を有する細胞が抗腫瘍免疫における重要な役割を担うことも示唆している。TRM分化に関しては比較的にほとんど知られておらず、内因性組織常在メモリー細胞は単離するのが困難であることで、基礎研究におけるそれらの試験及び養子細胞療法におけるそれらの応用が妨げられる。したがって、組織常在メモリー細胞を生成するための方法についての要求は満たされていない。
本明細書で用いられるとき、「本質的に含まない」は、特定成分の観点で、特定成分のいずれもが組成物中に意図的に配合されておらず、且つ/又はあくまで汚染物質として又は微量に存在することを意味するように本明細書で用いられる。それ故、組成物の任意の意図されない汚染に起因する特定成分の総量は、0.05%より十分に少なく、好ましくは0.01%未満である。特定成分の量が標準的分析法により検出できないような組成物が最も好ましい。
いくつかの実施形態では、本開示は、養子細胞療法のための方法であって、本開示のTRM細胞を有効量で投与することを含む方法を提供する。本開示の特定の実施形態では、がん又はウイルス性疾患は、免疫応答を誘発するTRM細胞集団の養子移植により処置される。いくつかの実施形態では、TRM細胞集団自体が、免疫応答を媒介することになる。TRM細胞は、一旦インビボで活性化すると、免疫応答を誘発することになる様々な炎症促進性因子、例えばケモカイン及びサイトカインを生成することがある。個体におけるがんの進行を処置するか又は遅延させるための方法であって、TRM細胞集団を有効量で個体に投与することを含む方法が本明細書に提供される。本方法は、免疫異常、固形がん、血液がん、及びウイルス感染を処置するため、適用されてもよい。例えば、実施形態による処置の対象のウイルス感染は、HIV、HBV又はヘルペスウイルス感染であってもよい。
特定の実施形態では、本明細書に提供される方法は、少なくとも1つの追加的な治療薬を対象に投与するステップをさらに含む。本明細書で開示されるすべての追加的な治療薬は、任意の潜在的毒性、起こり得る副作用、及び任意の他の関連する要因を考慮する、各々の具体的な組成物又は治療法に対する優良臨床試験基準に従い、対象に投与されることになる。
別の態様では、TRM細胞及び薬学的に許容できる担体を含む医薬組成物及び製剤が本明細書に提供される。
いくつかの実施形態では、例えばTRM細胞を生成するための1つ以上の培地及び成分を含み得るキットが提供される。かかる配合物は、TRM細胞との組み合わせに適した形態で因子のカクテルを含んでもよい。試薬系は、必要に応じて、水性培地又は凍結乾燥形態のいずれかでパッケージングされてもよい。キットの容器手段は、一般に、少なくとも1つのバイアル、試験管、フラスコ、ボトル、シリンジ又は他の容器手段を含むことになり、その中に成分が入れられ、好ましくは好適にアリコートされてもよい。キット内に2つ以上の成分が存在する場合、キットはまた、一般に、第2の、第3の又は他の追加的な容器を含むことになり、その中に追加的な成分が別々に入れられてもよい。しかし、成分の様々な組み合わせが、バイアル中に含まれてもよい。キットの成分は、乾燥粉末として提供されてもよい。試薬及び/又は成分が乾燥粉末として提供されるとき、粉末は、好適な溶媒の添加により再構成され得る。溶媒も別の容器手段で提供されてよいことが想定される。キットはまた、典型的には、市販用に密封された、キット成分を含有するための手段を含むことになる。かかる容器は、注射又はブロー成形プラスチック容器を含んでもよく、その中に所望されるバイアルが保持される。キットはまた、使用説明書を、例えば印刷又は電子フォーマット、例えばデジタルフォーマットで含み得る。
以下の実施例は、本発明の好ましい実施形態を実証するために含められる。以下の実施例中に開示される技術が、本発明の実施において十分に機能することが発明者によって発見された技術を表し、それ故、その実施における好ましいモードを構成することが考察できることは当業者によって理解される必要がある。しかし、当業者は、本開示に照らして、開示される具体的な実施形態において多数の変化を設けることができることを理解するだけでなく、本発明の精神及び範囲から逸脱することなく同様又は類似の結果を得る必要がある。
末梢血サンプルを健常ヒト対象から得た。FACSを使用して血液を選別し、ナイーブ(CD45RA+CCR7+)CD8+T細胞を単離した。次に、T細胞を多クローン性に大気酸素下(約20%)又は低酸素下(2%O2)で4日間活性化させ、「初期エフェクター」を生成した。次に、初期エフェクターを1.25ng/mLのrhTGF-β1の存在下でさらに2日間培養した。次に細胞を収集し、TRM関連遺伝子及び表面マーカーの発現について分析した。
細胞単離及びインビトロ細胞培養:健常なドナー末梢血単核球(PBMC)を白血球除去により収集し、使用まで液体窒素中で貯蔵した。すべてのヒトサンプル収集は、インフォームドコンセントを得て実施し、UT MD Anderson Cancer Centerの機関審査委員会(IRB)により承認された。StemCell EasySep(商標)キットを使用し、CD8+T細胞を健常ドナーPBMCから濃縮した。次に、CD8、CD45RA、及びCCR7に対する蛍光色素コンジュゲート抗体で細胞を染色した。FACSAria(商標)III又はFusionセルソーター(BD Biosciences)を使用し、ナイーブCD8+CD45RA+CCR7+細胞を選別した。選別されたナイーブ細胞を、10IU/mlのIL-2(Prometheus)を有する細胞培地(10%FBS、L-グルタミン、及びペニシリン-ストレプトマイシンを有するRPMI)に再懸濁し、低酸素チャンバー(Coy Laboratory Products)内の2%酸素又は標準細胞培養インキュベーター(Thermo Fisher)内の大気酸素(約20%)に一晩平衡化した。平衡化後、抗CD3/抗CD28ビーズ(Dynabeads(登録商標),Gibco)で細胞を4日間活性化させた。4日目、1.25ng/mlの組換えヒトTGF-β1(Biolegend)を添加し、細胞をさらに2日間培養した。自己ペプチドパルス樹状細胞による刺激又はTCR形質導入とその後の四量体に基づく選別を介して生成された抗原特異的CD8+T細胞を、通常の急速拡大プロトコル(REP)又はTRM修飾REPを用いて拡大した。30ng/mLの抗CD3(OKT3)を使用し、四量体陽性細胞を10~14日間拡大し、i)20%酸素と通常のREPの場合にIL-2(50IU/ml)の添加、又はii)2%酸素と修飾REPの場合にIL-15(10ng/ml)及びrhTGF-β1(1.25ng/ml、4日目開始)の添加のいずれかの下で、支持細胞として同種PBMC及びLCLに200回照射し、TRM表現型を誘導した。
低酸素及びTGF-β1下で分化したヒトCD8+T細胞はTRM様表現型を得る:炎症性組織内での相対的低酸素という条件で、低酸素圧がTRM分化へのさらなる要因をもたらし得ることが仮定された。低酸素がTRM表現型の誘導に寄与し得るか否かを判定するため、ナイーブ(CD45RA+CCR7+)CD8+T細胞をヒト末梢血から選別し、それらを低酸素下(2%O2)又は正常な細胞培養条件下(大気酸素、約20%O2)で4日間活性化し、「初期エフェクター」を生成し、次にrhTGF-β1の存在下でさらに2日培養した。
参考文献
以下の参考文献は、本明細書における提示を補足する、例示的な手順又は他の詳細を提供する程度まで、参照により本明細書中に具体的に援用される。
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Claims (124)
- 組織常在メモリー様T細胞(TRM様T細胞)を生成するためのインビトロ方法であって、
(a)T細胞の開始集団を得ることと;
(b)初期エフェクター細胞を生成するため、T細胞の前記開始集団を低酸素条件下又は低酸素誘導剤の存在下で培養することと;
(c)TRM様T細胞を生成するため、前記初期エフェクター細胞をトランスフォーミング成長因子β1(TGF-β1)の存在下でさらに培養することと、
を含む方法。 - 前記開始集団の前記T細胞が、CD8+末梢血T細胞である、請求項1に記載の方法。
- 前記CD8+末梢血T細胞が、ヒトCD8+末梢血T細胞である、請求項2に記載の方法。
- 前記ヒトCD8+末梢血T細胞を得ることが、末梢血サンプルからCD45RA+CCR7+CD8+ナイーブT細胞について選択することを含む、請求項3に記載の方法。
- 前記末梢血サンプルが、健常対象から得られる、請求項4に記載の方法。
- 前記末梢血サンプルが、がんと診断された対象又はがんを有することが疑われている対象から得られる、請求項4に記載の方法。
- 前記末梢血サンプルが、ウイルス性疾患と診断された対象又はウイルス性疾患を有することが疑われている対象から得られる、請求項4に記載の方法。
- 前記開始集団の前記T細胞が、培養前に、ペプチド、完全長抗原又は細胞ライセートでパルスされた抗原提示細胞により刺激される、請求項1に記載の方法。
- 前記T細胞が、腫瘍部位から得られるか、又は腫瘍浸潤リンパ球である、請求項8に記載の方法。
- 前記T細胞が、ナイーブT細胞である、請求項9に記載の方法。
- 前記細胞ライセートが、腫瘍ライセートである、請求項8に記載の方法。
- 前記抗原が、がん抗原又はウイルス抗原である、請求項8に記載の方法。
- 前記ペプチドが、がん細胞により差次的に発現されるか又は高度に発現されるタンパク質に由来するペプチドである、請求項8に記載の方法。
- 前記ペプチドが、ネオ抗原に由来するか又は突然変異を含むタンパク質に由来するペプチドである、請求項8に記載の方法。
- T細胞の前記開始集団が、目的の抗原に特異的なT細胞について濃縮される、請求項8に記載の方法。
- T細胞の前記開始集団が、CD8陽性及びペプチドMHC四量体陽性である細胞について濃縮するため、精製される、請求項8に記載の方法。
- T細胞の前記開始集団が、蛍光標識細胞分取により精製される、請求項16に記載の方法。
- T細胞の前記開始集団が、改変されたT細胞の集団である、請求項1に記載の方法。
- 前記改変されたT細胞が、クローン化T細胞受容体(TCR)の宿主細胞の集団への導入により生成される、請求項18に記載の方法。
- 前記宿主細胞が、末梢血単核球である、請求項19に記載の方法。
- 前記クローン化TCRが、非ウイルス的方法により、宿主細胞の前記集団に導入される、請求項19に記載の方法。
- 前記クローン化TCRが、エピソームベクター又はトランスポゾンにより、宿主細胞の前記集団に導入される、請求項21に記載の方法。
- 前記クローン化TCRが、形質導入により、宿主細胞の前記集団に導入される、請求項19に記載の方法。
- 宿主細胞の前記集団が、TCRα鎖及びTCRβ鎖を含むウイルスベクターにより形質導入される、請求項23に記載の方法。
- 前記ウイルスベクターが、レンチウイルスベクターである、請求項24に記載の方法。
- 宿主細胞の前記形質導入集団が、CD8陽性/ペプチドMHC四量体陽性細胞について濃縮するため、精製される、請求項24に記載の方法。
- 前記改変されたT細胞が、キメラ抗原受容体を発現する、請求項18に記載の方法。
- 前記キメラ抗原受容体が、がん抗原、ウイルス抗原、ネオ抗原又は突然変異を含むタンパク質からのペプチドに特異的に結合する抗原認識ドメインを含む、請求項27に記載の方法。
- 前記開始集団の前記T細胞が、対象から得られる腫瘍浸潤リンパ球である、請求項1に記載の方法。
- 低酸素条件が、5%未満の酸素としてさらに定義される、請求項1に記載の方法。
- 低酸素条件が、2%酸素としてさらに定義される、請求項1に記載の方法。
- 前記低酸素誘導剤が、低酸素模倣物である、請求項1に記載の方法。
- 前記低酸素誘導剤又は低酸素模倣物が、塩化コバルト(CoCl2)、デフェロキサミンメシル酸塩(DFOM)、ジメチルオキサリルグリシン(dimethyloxalyglycine)(DMOG)、又はプロリルヒドロキシラーゼ阻害剤である、請求項32に記載の方法。
- 前記プロリルヒドロキシラーゼ阻害剤が、2-OG類似体である、請求項33に記載の方法。
- 前記プロリルヒドロキシラーゼ阻害剤が、ロキサデュスタット(FG-4592)である、請求項33に記載の方法。
- ステップ(b)の培養が、前記TCR刺激及び同時刺激の存在下で実施される、請求項1に記載の方法。
- 前記TCR刺激及び同時刺激が、抗CD3及び抗CD28抗体、抗CD3及び抗CD28ビーズ、支持細胞、抗原提示細胞、人工抗原提示細胞、ペプチド及び/若しくはタンパク質抗原、又はそれらの組み合わせを含む、請求項36に記載の方法。
- 前記TCR刺激及び同時刺激が、抗CD3及び抗CD28ビーズを含む、請求項36に記載の方法。
- ステップ(b)の培養が、3~5日間実施される、請求項1に記載の方法。
- ステップ(b)の培養が、4日間実施される、請求項1に記載の方法。
- ステップ(c)の培養が、IL-15の存在下で実施される、請求項36に記載の方法。
- 前記IL-15が、5~20ng/mLの濃度で存在する、請求項41に記載の方法。
- 前記IL-15が、10ng/mLの濃度で存在する、請求項41に記載の方法。
- TGF-β1が、組換えヒトTGF-β1(rhTGF-β1)としてさらに定義される、請求項1に記載の方法。
- 前記rhTGF-β1が、0.1~5ng/mLの濃度で存在する、請求項44に記載の方法。
- 前記rhTGF-β1が、1~1.5ng/mLの濃度で存在する、請求項45に記載の方法。
- 前記rhTGF-β1が、1.25ng/mLの濃度で存在する、請求項45に記載の方法。
- ステップ(c)の培養が、低酸素条件下又は低酸素誘導剤の存在下で実施される、請求項1に記載の方法。
- ステップ(c)の培養が、IL-15の存在下で実施される、請求項48に記載の方法。
- 前記IL-15が、5~20ng/mLの濃度で存在する、請求項49に記載の方法。
- 前記IL-15が、10ng/mLの濃度で存在する、請求項49に記載の方法。
- ステップ(c)の培養が、1~3日間実施される、請求項1に記載の方法。
- ステップ(c)の培養が、2日間実施される、請求項1に記載の方法。
- 前記TRM様T細胞が、CD69+CD103+である、請求項1に記載の方法。
- ステップ(c)で生成された前記細胞の少なくとも30%が、CD69+CD103+細胞である、請求項54に記載の方法。
- ステップ(c)で生成された前記細胞の少なくとも40%が、CD69+CD103+細胞である、請求項54に記載の方法。
- 前記TRM様T細胞が、PD-1、CD101、及び/又はCD49aを発現する、請求項1に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、CD69、ITGAE、PDCD1及び/又はCD101のより高い発現を有する、請求項1に記載の方法。
- CD69、ITGAE、PDCD1及び/又はCD101の前記より高い発現が、CD69、ITGAE、PDCD1、及び/又はCD101 mRNA転写物のより高い発現である、請求項58に記載の方法。
- CD69、ITGAE、PDCD1及び/又はCD101の前記より高い発現が、CD69、ITGAE、PDCD1及び/又はCD101タンパク質のより高い発現である、請求項58に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、TNFα、GZMB、SLC2A1、及び/又はVEGFのより高い発現を有する、請求項1に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、GNLY、MYO7A、ITGAE、EGR2、CCL20、ATP1B1、NR4A3、PERP、RASGEF1B、NR4A1、BMF、EGR1、CXCL13、PDCD1、ITGA1、CCL22、CA10、RGS1、ITGA1、CD101、TNFRSF9(4-1BB)、CCL4、CCL5、NOTCH1、RBPJ、STRIP2、ARHGEF40、DBH、SRGAP3、CSGALNACT1、GPR25、RGS16、DAPK2、NCS1、COL6A3、GDPD4、SLC1A4、CDK14、LMCD1、ILDR2、及び/又はADCY3のより高い発現を有する、請求項1に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、GNLY、MYO7A、ITGAE、EGR2、CCL20、ATP1B1、NR4A3、PERP、RASGEF1B、NR4A1、BMF、EGR1、CXCL13、PDCD1、ITGA1、CCL22、CA10、及び/又はRGS1のより高い発現を有する、請求項62に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、ITGAE、ITGA1、PDC1、CD101、TNFRSF9(4-1BB)、CXCL13、CCL20、NOTCH1、RBPJ、NR4A1、EGR2、及び/又はRGS1のより高い発現を有する、請求項62に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、MYO7A、STRIP2、ARHGEF40、ITGAE、DBH、SRGAP3、CSGALNACT1、GPR25、RGS16、DAPK2、NCS1、COL6A3、GDPD4、SLC1A4、CXCL13、CDK14、LMCD1、ILDR2、及び/又はADCY3のより高い発現を有する、請求項62に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、CD58、NR3C1、RAP1GAP2、SELP、CXCR2、TBX21、ITGAL、SELL、KLF3、KLF2、RASGRP2、FAM65B、SERPINE2、ITGAM、KLRB1、TGFBR3、SMAD3、TNFSF8、DUSP2、PLEK、GOLGA2P7、FOSB、PLCG2、SLAMF7、SLC6A8、SOCS3、及び/又はPTGER2のより低い発現を有する、請求項1に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、CD58、NR3C1、RAP1GAP2、SELP、CXCR2、TBX21、ITGAL、SELL、KLF3、RASGRP2、ITGAM、KLRB1、TGFBR3、SMAD3、及び/又はTNFSF8のより低い発現を有する、請求項66に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、KLF2、KLF3、SELL、FAM65B、及び/又はSERPINE2のより低い発現を有する、請求項66に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、DUSP2、PLEK、GOLGA2P7、FOSB、PLCG2、ITGAM、FOS、KLF3、SLAMF7、TNFSF8、SLC6A8、KLF2、SOCS3、及び/又はPTGER2のより低い発現を有する、請求項66に記載の方法。
- 前記TRM様T細胞が、大気酸素条件下で培養された細胞と比べて、S1PR1、KLF4及び/又はSELLの減少した発現を有する、請求項1に記載の方法。
- 前記TRM様T細胞が、CXCR6タンパク質の発現を本質的に有しない、請求項1に記載の方法。
- 前記TRM様T細胞が、抗原特異的である、請求項1に記載の方法。
- 抗原特異的なTRM様T細胞を生成することをさらに含む、請求項1に記載の方法。
- 抗原特異的なTRM様T細胞を生成することが、抗原特異的T細胞受容体(TCR)を前記TRM様T細胞に形質導入することを含む、請求項73に記載の方法。
- 抗原特異的なTRM様T細胞を生成することが、ステップ(b)中に、T細胞の前記開始集団をペプチドパルス抗原提示細胞(APC)とともに培養することを含む、請求項73に記載の方法。
- 前記APCが、成熟樹状細胞である、請求項75に記載の方法。
- 前記APCが、人工APC(aAPC)である、請求項75に記載の方法。
- ステップ(b)及び(c)が、少なくとも1回反復される、請求項77に記載の方法。
- 抗原特異的なTRM様T細胞を生成することが、ステップ(b)及び/又はステップ(c)中、前記細胞をヒストンデアセチラーゼ(HDAC)阻害剤の存在下で培養することを含む、請求項73に記載の方法。
- 前記HDAC阻害剤が、トリコスタチンA、トラポキシンB、フェニル酪酸、バルプロ酸、ボリノスタット(スベラニロヒドロキサム酸又はSAHA、Zolinza(登録商標)として市販)、ベリノスタット(PXD101、Beleodaq(登録商標)として市販)、パノビノスタット(Farydaq(登録商標)として市販)、ダシノスタット(LAQ824)、エンチノスタット(SNDX-275又はMS-275)、タセジナリン(CI994)、及びモセチノスタット(MGCD0103)からなる群から選択される、請求項79に記載の方法。
- CXCR6タンパク質の発現を本質的に有しないTRM様T細胞。
- 請求項1~80のいずれか一項に記載の方法によって生成される、請求項81に記載のTRM様T細胞。
- PD-1、CD101、及び/又はCD49aを発現する、請求項81に記載のTRM様T細胞。
- CD69+CD103+である、請求項81に記載のTRM様T細胞。
- GNLY、MYO7A、ITGAE、EGR2、CCL20、ATP1B1、NR4A3、PERP、RASGEF1B、NR4A1、BMF、EGR1、CXCL13、PDCD1、ITGA1、CCL22、CA10、RGS1、ITGA1、CD101、TNFRSF9(4-1BB)、CCL4、CCL5、NOTCH1、RBPJ、STRIP2、ARHGEF40、DBH、SRGAP3、CSGALNACT1、GPR25、RGS16、DAPK2、NCS1、COL6A3、GDPD4、SLC1A4、CDK14、LMCD1、ILDR2、及び/又はADCY3を発現する、請求項81に記載のTRM様T細胞。
- GNLY、MYO7A、ITGAE、EGR2、CCL20、ATP1B1、NR4A3、PERP、RASGEF1B、NR4A1、BMF、EGR1、CXCL13、PDCD1、ITGA1、CCL22、CA10、及び/又はRGS1を発現する、請求項81に記載のTRM様T細胞。
- ITGAE、ITGA1、PDCD1、CD101、TNFRSF9(4-1BB)、CXCL13、CCL20、NOTCH1、RBPJ、NR4A1、EGR2、及び/又はRGS1を発現する、請求項81に記載のTRM様T細胞。
- MYO7A、STRIP2、ARHGEF40、ITGAE、DBH、SRGAP3、CSGALNACT1、GPR25、RGS16、DAPK2、NCS1、COL6A3、GDPD4、SLC1A4、CXCL13、CDK14、LMCD1、ILDR2、及び/又はADCY3を発現する、請求項81に記載のTRM様T細胞。
- CD58、NR3C1、RAP1GAP2、SELP、CXCR2、TBX21、ITGAL、SELL、KLF3、KLF2、RASGRP2、FAM65B、SERPINE2、ITGAM、KLRB1、TGFBR3、SMAD3、TNFSF8、DUSP2、PLEK、GOLGA2P7、FOSB、PLCG2、SLAMF7、SLC6A8、SOCS3、及び/又はPTGER2を発現しないか又はそれらの発現を本質的に有しない、請求項81に記載のTRM様T細胞。
- CD58、NR3C1、RAP1GAP2、SELP、CXCR2、TBX21、ITGAL、SELL、KLF3、RASGRP2、ITGAM、KLRB1、TGFBR3、SMAD3、及び/又はTNFSF8を発現しないか又はそれらの発現を本質的に有しない、請求項81に記載のTRM様T細胞。
- KLF2、KLF3、SELL、FAM65B、及び/又はSERPINE2を発現しないか又はそれらの発現を本質的に有しない、請求項81に記載のTRM様T細胞。
- DUSP2、PLEK、GOLGA2P7、FOSB、PLCG2、ITGAM、FOS、KLF3、SLAMF7、TNFSF8、SLC6A8、KLF2、SOCS3、及び/又はPTGER2を発現しないか又はそれらの発現を本質的に有しない、請求項81に記載のTRM様T細胞。
- CXCR6タンパク質の発現を本質的に伴わず、且つ薬学的に許容できる担体を有するTRM様T細胞の集団を含む医薬組成物。
- 前記TRM様T細胞が、請求項1~80のいずれか一項に記載の方法により生成される、請求項93に記載の組成物。
- 前記TRM様T細胞が、PD-1、CD101、及び/又はCD49aを発現する、請求項93に記載の組成物。
- 前記細胞の少なくとも40%が、CD69+CD103+細胞である、請求項93に記載の組成物。
- TRM様T細胞が、CD69+CD103+細胞である、請求項93に記載の組成物。
- TRM様T細胞が、GNLY、MYO7A、ITGAE、EGR2、CCL20、ATP1B1、NR4A3、PERP、RASGEF1B、NR4A1、BMF、EGR1、CXCL13、PDCD1、ITGA1、CCL22、CA10、RGS1、ITGA1、CD101、TNFRSF9(4-1BB)、CCL4、CCL5、NOTCH1、RBPJ、STRIP2、ARHGEF40、DBH、SRGAP3、CSGALNACT1、GPR25、RGS16、DAPK2、NCS1、COL6A3、GDPD4、SLC1A4、CDK14、LMCD1、ILDR2、及び/又はADCY3を発現する、請求項93に記載の組成物。
- 前記TRM様T細胞が、GNLY、MYO7A、ITGAE、EGR2、CCL20、ATP1B1、NR4A3、PERP、RASGEF1B、NR4A1、BMF、EGR1、CXCL13、PDCD1、ITGA1、CCL22、CA10、及び/又はRGS1を発現する、請求項93に記載の組成物。
- 前記TRM様T細胞が、ITGAE、ITGA1、PDC1、CD101、TNFRSF9(4-1BB)、CXCL13、CCL20、NOTCH1、RBPJ、NR4A1、EGR2、及び/又はRGS1を発現する、請求項93に記載の組成物。
- 前記TRM様T細胞が、MYO7A、STRIP2、ARHGEF40、ITGAE、DBH、SRGAP3、CSGALNACT1、GPR25、RGS16、DAPK2、NCS1、COL6A3、GDPD4、SLC1A4、CXCL13、CDK14、LMCD1、ILDR2、及び/又はADCY3を発現する、請求項93に記載の組成物。
- 前記TRM様T細胞が、CD58、NR3C1、RAP1GAP2、SELP、CXCR2、TBX21、ITGAL、SELL、KLF3、KLF2、RASGRP2、FAM65B、SERPINE2、ITGAM、KLRB1、TGFBR3、SMAD3、TNFSF8、DUSP2、PLEK、GOLGA2P7、FOSB、PLCG2、SLAMF7、SLC6A8、SOCS3、及び/又はPTGER2を発現しないか又はそれらの発現を本質的に有しない、請求項93に記載の組成物。
- 前記TRM様T細胞が、CD58、NR3C1、RAP1GAP2、SELP、CXCR2、TBX21、ITGAL、SELL、KLF3、RASGRP2、ITGAM、KLRB1、TGFBR3、SMAD3、及び/又はTNFSF8を発現しないか又はそれらの発現を本質的に有しない、請求項93に記載の組成物。
- 前記TRM様T細胞が、KLF2、KLF3、SELL、FAM65B、及び/又はSERPINE2を発現しないか又はそれらの発現を本質的に有しない、請求項93に記載の組成物。
- 前記TRM様T細胞が、DUSP2、PLEK、GOLGA2P7、FOSB、PLCG2、ITGAM、FOS、KLF3、SLAMF7、TNFSF8、SLC6A8、KLF2、SOCS3、及び/又はPTGER2を発現しないか又はそれらの発現を本質的に有しない、請求項93に記載の組成物。
- 対象における免疫関連障害を処置するための、CXCR6タンパク質の発現を本質的に伴わないTRM様T細胞を有効量で含む組成物。
- 前記TRM様T細胞が、請求項1~80のいずれか一項に記載の方法により生成される、請求項106に記載の組成物。
- 対象における免疫関連障害を処置するための、CXCR6タンパク質の発現を本質的に伴わないTRM様T細胞の有効量での使用。
- 前記TRM様T細胞が、請求項1~80のいずれか一項に記載の方法により生成される、請求項108に記載の使用。
- 対象における免疫関連障害を処置する方法であって、請求項1~80のいずれか一項に記載の方法によって生成されたTRM様T細胞を有効量で前記対象に投与することを含む方法。
- 前記免疫関連障害が、がん、自己免疫不全、移植片対宿主病、同種移植片拒絶、又は炎症性状態である、請求項110に記載の方法。
- 前記対象が、組織又は臓器移植を受けている、請求項111に記載の方法。
- 少なくとも第2の治療薬を投与することをさらに含む、請求項110に記載の方法。
- 前記少なくとも第2の治療薬が、化学療法、免疫療法、手術、放射線療法、又は生物学的療法を含む、請求項113に記載の方法。
- 前記TRM様T細胞及び/又は前記少なくとも第2の治療薬が、静脈内に、腹腔内に、気管内に、腫瘍内に、筋肉内に、内視鏡的に、病変内に、経皮的に、皮下に、局所性に、又は直接注射若しくは灌流により投与される、請求項113に記載の方法。
- 前記TRM様T細胞が、前記第2の治療薬の前に投与される、請求項113に記載の方法。
- 前記TRM様T細胞が、前記第2の治療薬の後に投与される、請求項113に記載の方法。
- 前記TRM様T細胞が、前記第2の治療薬と同時に投与される、請求項113に記載の方法。
- 前記免疫療法が、4-1BB作動薬である、請求項114に記載の方法。
- 前記4-1BB作動薬が、4-1BB抗体である、請求項120に記載の方法。
- 前記免疫療法が、免疫チェックポイント療法である、請求項114に記載の方法。
- 前記免疫チェックポイント療法が、CTLA-4、PD-1、又はPD-L1の遮断又は阻害である、請求項121に記載の方法。
- 前記対象が、ヒトである、請求項110に記載の方法。
- 対象におけるウイルス感染を処置する方法であって、請求項1~80のいずれか一項に記載の方法によって生成されたTRM様T細胞を有効量で前記対象に投与することを含む、方法。
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